We undertook a Phase I study of anti-CD3 monoclonal antibodies in patients with solid tumors to determine the toxicity and immunomodulatory properties of this antibody at various doses and schedules. Initially, the protocol was designed to treat five patients at one of six dose levels including 1, 10, 30, 100, 300 and 1,000 micrograms (mog) per patient. Patients received four doses by three-hour infusion over two weeks. Dose-limiting toxicity occurred in all three patients at 100 mog of anti-CD3 and further dose escalation was discontinued. Dose-limiting toxicity consisted of severe headache associated with a syndrome of aseptic meningitis. Cerebrospinal fluid showed an abnormal lymphocytosis with an elevated protein. Thus, the maximum tolerated dose of anti-CD3 by three-hour infusion was 30 mog. An additional five patients received 30 mog by bolus injection according to the same immunologic data failed to reveal marked changes according to this schedule. Because of the toxicity at lack of immunologic effects when anti-CD3 is administered according to this schedule, we changed to daily administration for 14 days. We treated five patients with three mog of anti-CD3 by bolus and two by three-hour infusion. Severe headache was seen in both patients receiving 3 mog by three-hour infusion and in 1/5 patients receiving bolus administration. Toxicity appears to be related to the dose, duration of infusion and frequency of anti-CD3 administration.